Pyrrolidinedione substituted piperidine-phthalazones as PDE4 inhibitors

ABSTRACT

The compounds of formula I 
                         
in which the substituents have the meanings as indicated in the description, are novel effective PDE4 inhibitors.

FIELD OF APPLICATION OF THE INVENTION

The invention relates to novel piperidine-derivatives, which are used inthe pharmaceutical industry for the production of pharmaceuticalcompositions.

KNOWN TECHNICAL BACKGROUND

International Patent Applications WO98/31674 (=U.S. Pat. No. 6,103,718),WO99/31071, WO99/31090, WO99/47505 (=U.S. Pat. No. 6,255,303),WO01/19818, WO01/30766, WO01/30777, WO01/94319, WO02/064584, WO02/085885and WO02/085906 disclose phthalazinone derivatives having PDE4inhibitory properties. In the International Patent ApplicationWO94/12461 and in the European Patent Application EP 0 7635343-aryl-pyridazin-6-one and arylalkyl-diazinone derivatives aredescribed as selective PDE4 inhibitors. International Patent ApplicationWO93/07146 (=U.S. Pat. No. 5,716,954) discloses benzo and pyridopyridazinone and pyridazinthione compounds with PDE4 inhibitingactivity.

In the Journal of Medicinal Chemistry, Vol. 33, No. 6, 1990, pp.1735–1741 1,4-Bis(3-oxo-2,3-dihydropyridazin-6-yl)benzene derivativesare described as potent phosphodiesterase inhibitors and inodilators. Inthe Journal of Medicinal Chemistry Vol. 45 No.12, 2002, pp. 2520–2525,2526–2533 and in Vol. 44, No. 16, 2001, pp. 2511–2522 and pp. 2523–2535phthalazinone derivatives are described as selective PDE4 inhibitors.

DESCRIPTION OF THE INVENTION

It has now been found that the piperidine-derivatives, which aredescribed in greater details below, have surprising and particularlyadvantageous properties.

The invention thus relates to compounds of formula 1

in which

-   R1 and R2 are both hydrogen or together form an additional bond,-   R3 represents a phenyl derivative of formulae (a) or (b)

-   wherein    -   R4 is 1–4C-alkoxy or 1–4C-alkoxy which is completely or        predominantly substituted by fluorine,    -   R5 is 1–4C-alkoxy, 3–7C-cycloalkoxy, 3–7C-cycloalkylmethoxy, or        1–4C-alkoxy which is or predominantly substituted by fluorine,    -   R6 is 1–4C-alkoxy or 1–4C-alkoxy which is completely or        predominantly substituted by fluorine,    -   R7 is 1–4C-alkyl and    -   R8 is hydrogen or 1–4C-alkyl,    -   or wherein    -   R7 and R8 together and with inclusion of the two carbon atoms,        to which they are bonded, form a spiro-linked 5-, 6- or        7-membered hydrocarbon ring, optionally interrupted by an oxygen        or sulphur atom,-   R9 is —C(O)—(CH₂)_(n)—R10,    -   wherein    -   R10 is pyrrolidine-2,5-dione-1-yl,    -   n is an integer from 1 to 4,        and the salts of these compounds.

If R1 and R2 together are an additional bond, then the carbon atoms inthe positions 6 and 7 in the hexahydro-phthalazinone ring system of thecompounds of formula 1 are linked to one another via a double bond(→tetrahydrophthalazinone ring system).

1–4C-Alkyl is a straight-chain or branched alkyl radical having 1 to 4carbon atoms. Examples are the butyl, isobutyl, sec-butyl, tert-butyl,propyl, isopropyl, ethyl and methyl radicals.

1–4C-Alkoxy is a radical which in addition to the oxygen atom, containsa straight-chain or branched alkyl radical having 1 to 4 carbon atoms.Alkoxy radicals having 1 to 4 carbon atoms which may be mentioned inthis context are, for example, the butoxy, isobutoxy, sec-butoxy,tert-butoxy, propoxy, isopropoxy, ethoxy and methoxy radicals. Preferredare the methoxy and ethoxy radicals.

1–4C-Alkoxy which is completely or predominantly substituted by fluorineis, for example, the 2,2,3,3,3-pentafluoropropoxy, the perfluoroethoxy,the 1,2,2-trifluoroethoxy and in particular the1,1,2,2-tetrafluoroethoxy, the 2,2,2-trifluoroethoxy, thetrifluoromethoxy and the difluoromethoxy radical, of which thedifluoromethoxy radical is preferred. “Predominantly” in this connectionmeans that more than half of the hydrogen atoms of the 1–4C-alkoxy groupare replaced by fluorine atoms.

3–7C-Cycloalkoxy stands for cyclopropyloxy, cyclobutyloxy,cyclopentyloxy, cyclohexyloxy or cycloheptyloxy, of whichcyclopropyloxy, cyclobutyloxy and cyclopentyloxy are preferred.

3–7C-Cycloalkylmethoxy stands for cyclopropylmethoxy, cyclobutylmethoxy,cyclopentylmethoxy, cyclohexylmethoxy or cycloheptylmethoxy, of whichcyclopropylmethoxy, cyclobutylmethoxy and cyclopentylmethoxy arepreferred.

As spiro-linked 5-, 6- or 7-membered hydrocarbon rings, optionallyinterrupted by an oxygen or sulphur atom, may be mentioned thecyclopentane, cyclohexane, cycloheptane, tetrahydrofuran,tetrahydropyran and the tetrahydrothiophen ring.

Suitable salts for compounds of the formula 1 are all acid additionsalts. Particular mention may be made of the pharmacologically tolerableinorganic and organic acids customarily used in pharmacy. Those suitableare water-soluble and water-insoluble acid addition salts with acidssuch as, for example, hydrochloric acid, hydrobromic acid, phosphoricacid, nitric acid, sulphuric acid, acetic acid, citric acid, D-gluconicacid, benzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, butyric acid,sulphosalicylic acid, maleic acid, lauric acid, malic acid, fumaricacid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearicacid, toluenesulphonic acid, methanesulphonic acid or3-hydroxy-2-naphthoic acid, the acids being employed in saltpreparation—depending on whether a mono- or polybasic acid is concernedand depending on which salt is desired—in an equimolar quantitativeratio or one differing therefrom.

Pharmacologically intolerable salts, which can be obtained, for example,as process products during the preparation of the compounds according tothe invention on an industrial scale, are converted intopharmacologically tolerable salts by processes known to the personskilled in the art.

According to expert's knowledge the compounds of the invention as wellas their salts may contain, e.g. when isolated in crystalline form,varying amounts of solvents. Included within the scope of the inventionare therefore all solvates and in particular all hydrates of thecompounds of formula 1 as well as all solvates and in particular allhydrates of the salts of the compounds of formula 1.

Compounds of formula 1 to be emphasized are those in which

-   R1 and R2 are both hydrogen or together form an additional bond,-   R3 represents a phenyl derivative of formulae (a) or (b)

wherein

-   -   R4 is 1–2C-alkoxy or 1–2C-alkoxy which is completely or        predominantly substituted by fluorine,    -   R5 is 1–2C-alkoxy or 1–2C-alkoxy which is completely or        predominantly substituted by fluorine,    -   R6 is 1–2C-alkoxy or 1–2C-alkoxy which is completely or        predominantly substituted by fluorine,    -   R7 is methyl and    -   R8 is hydrogen,    -   or wherein    -   R7 and R8 together and with inclusion of the two carbon atoms,        to which they are bonded, form a spiro-linked cyclopentane,        cyclohexane, tetrahydrofurane or tetrahydropyran ring,

-   R9 is —C(O)—(CH₂)_(n)—R10,    -   wherein    -   R10 is pyrrolidine-2,5-dione-1-yl and    -   n is an integer from 1 to 2,        and the salts of these compounds.

Compounds of formula 1 to be particularly emphasized are those, in which

-   -   R1 and R2 together form an additional bond,    -   R3 represents a phenyl derivative of formula (a)

wherein

-   -   R4 is 1–2C-alkoxy,    -   R5 is 1–2C-alkoxy,

-   R9 is —C(O)—(CH₂)_(n)—R10,    -   wherein    -   R10 is pyrrolidine-2,5-dione-1-yl and    -   n is 1,        and the salts of these compounds.

Preferred compounds of formula 1 are those in which

-   -   R1 and R2 together form an additional bond,    -   R3 represents a phenyl derivative of formula (a)

wherein

-   -   R4 is methoxy,    -   R5 is methoxy,

-   R9 is —C(O)—(CH₂)_(n)—R10,    -   wherein    -   R10 is pyrrolidine-2,5-dione-1-yl and    -   n is 1,        and the salts of these compounds.

A special embodiment of the invention are those compounds of formula 1in which R3 represents a phenyl derivative of formula (a).

Another special embodiment of the invention are those compounds offormula 1 in which R3 represents a phenyl derivative of formula (a) andn is 1.

Still another special embodiment of the invention are those compounds offormula 1 in which R1 and R2 form an additional bond and R3 represents aphenyl derivative of formula (a).

A further special embodiment of the invention are compounds of formula 1in which R1 and R2 form an additional bond, R3 represents a phenylderivative of formula (a) and n is 1.

Still a further special embodiment of the invention are compounds offormula 1 in which R1 and R2 form an additional bond, R3 represents aphenyl derivative of formula (b), R6 is methoxy, R7 is methyl, R8 ishydrogen, or R7 and R8 together and with inclusion of the two carbonatoms to which they are bonded form a spiro-linked cyclopentane orcyclohexane ring, and n is 1.

The compounds of formula 1 are chiral compounds. Chiral centers exist inthe compounds of formula 1 in the positions 4a and 8a. In case R3represents a phenyl derivative of formula (b) there is one furtherchiral center in the dihydrofuran-ring, if the substituents —R7 and—CH₂R8 are not identical. However, preferred are in this connectionthose compounds, in which the substituents —R7 and —CH₂R8 are identicalor together and with inclusion of the two carbon atoms to which they arebonded form a spiro-connected 5-, 6- or 7-membered hydrocarbon ring.

Numbering:

Therefore the invention includes all conceivable pure diastereomers andpure enantiomers of the compounds of formula 1, as well as all mixturesthereof independent from the ratio, including the race-mates. Preferredare those compounds of formula 1, in which the hydrogen atoms in thepositions 4a and 8a are cis-configurated. Particularly preferred in thisconnection are those compounds, in which the absolute configuration(according to the rules of Cahn, Ingold and Prelog) is S in the position4a and R in the position 8a.

Racemates can be split up into the corresponding enantiomers by methodsknown by a person skilled in the art. Preferably the racemic mixturesare separated into two diastereomers during the preparation with thehelp of an optical active separation agent on the stage of thecyclohexanecarboxylic acids or the 1,2,3,6-tetrahydrobenzoic acids (forexample, starting compounds A8, A9 and A10).

As separation agents may be mentioned, for example, optical activeamines such as the (+)- and (−)-forms of 1-phenylethylamine[(R)-(+)-1-phenylethylamine=(R)-(+)-α-methylbenzylamine or(S)-(−)-1-phenylethylamine=(S)-(−)-α-methylbenzylamine) and ephedrine,the optical active alkaloids quinine, cinchonine, cinchonidine andbrucine.

The compounds according to the invention can be prepared, for example,as described In Reaction scheme 1.

Reaction scheme 1 shows that the compounds of formula 1 can be, forexample, prepared starting from 4-oxo-piperidine-1-carboxylic acidtert-butyl ester which is reacted in a first reaction step withtert-butylcarbazate to give4-(tert-Butoxycarbonyl-hydrazono)-piperidine-1-carboxylic acidtert-butyl ester (starting compound A7). Compound A7 is reduced with,for example, the boran tetrahydrofurane complex to give4-(N′-tert-Butoxycarbonyl-hydrazino)-piperidine-1-carboxylic acidtert-butyl ester (starting compound A6). Treatment of compound A6 withconcentrated hydrochloric acid results in the formation ofpiperldin-4-yl-hydrazine dihydrochloride (starting compound A5).

The reaction of piperidin-4-yl-hydrazine dihydrochloride withbenzoyl-1,2,3,6-tetrahydrobenzoic acids,benzoyl-1,2,3,4,5,6hexahydrobenzoic acids,2-[1-(2,3-dihydro-benzofuran-4-yl)methanoyl]-cyclohexane carboxylicacids or -cyclohexene carboxylic acids of formulae 4a or 4b leads to thepiperidino derivatives of formula 3.

The piperidino derivatives of formula 3 are reacted with chloroacetylchloride (3-chloropropionyl chloride, 4-chlorobutyryl chloride or5-chloropentanoyl chloride) to give compounds of formula 2, which fortheir part are reacted in the final reaction step withpyrrolidine-2,5-dione to give the compounds of formula 1.

The reaction of the piperidino derivatives of formula 3 withchloroacetyl chloride (3-chloropropionyl chloride, 4-chlorobutyrylchloride or 5-chloropentanoyl chloride) is, for example, carried out inan inert solvent like acetone or homologues, acetonitrile,tetrahydrofurane, benzene, toluene, dioxane, (di-)ethyleneglycol ethers,dichloromethane, chloroform or homologues, ethyl acetate or pyridine,preferably in acetone, ethyl acetate or dichloromethane, in the presenceof a suitable organic base, for example pyridine, quinoline,dimethylaniline, triethylamine or diisopropylethylamine, preferablytriethylamine. Alternatively, the reaction is carried out in a two phasesystem of a solvent of the above mentioned list and water with one ofthe aforementioned organic bases or in a two phase system of a solventof the abovementioned list and water containing an inorganic base suchas sodium (or potassium) carbonate, sodium (or potassium)hydrogencarbonate or sodium (or potassium) hydroxide with or without anadded quarternary alkylammonium phase transfer catalyst e.g.tetrabutylammonium chloride or a homologue thereof. In general, thereaction temperature is between −30 and +50° C., preferably the reactiontemperature is about 0° C.

The reaction of the compounds of formula 2 with pyrrolidine-2,5-dione iscarried out in a suitable inert solvent like acetone and homologues,acetonitrile, dimethylformamide, dimethylacetamide, N-methylpyrrolidone,dimethylsulfoxide, dioxane or diethylene glycol ethers, preferablydimethylformamide or butanone, in the presence of a suitable base, forexample potassium, sodium, calcium or barium hydroxide or potassium orsodium carbonate; the preferred base is potassium carbonate. Thereaction temperature can range from 0 to 150° C., preferred is areaction temperature between 20 and 100° C.

In a variation of the above-mentioned reaction conditions a suitablebasic salt of pyrrolidine-2,5-dione (for example, the potassium orsodium salt of pyrrolidine-2,5-dione) can be used directly instead ofpreparing it in situ by the addition of a suitable base topyrrolidine-2,5-dione in the reaction mixture.

In an alternative synthesis route, the compounds of formula 3 can bereacted with 1-(2-chloroethanoyl)-pyrrolidine-2,5-dione[1-(3-chloro-propanoyl)-pyrrolidine-2,5-dione,1-(4-chloro-butanoyl)-pyrrolidine-2,5-dione or 1-(5-chloropentanoyl)-pyrrolidine-2,5-dione] to yield the compounds of formula 1.

The reaction of the compounds of formula 3 with1-(2-chloro-ethanoyl)-pyrrolidine-2,5-dione[1-(3-chloro-propanoyl)-pyrrolidine-2,5-dione,1-(4-chloro-butanoyl)-pyrrolidine-2,5-dione or1-(5-chloro-pentanoyl)-pyrrolidine-2,5-dione] is carried out in asuitable inert solvent like acetone and homologues, acetonitrile,dimethylformamide, dimethylacetamide, N-methylpyrrolidone,dimethylsulfoxide, dioxane or diethylene glycol ethers, preferablydimethylformamide or butanone, in the presence of a suitable base, forexample potassium, sodium, calcium or barium hydroxide or potassium orsodium carbonate; the preferred base is potassium carbonate. Thereaction temperature can range from 0 to 150° C., preferred is areaction temperature between 20 and 100° C.

The compounds of formula 1 prepared by the processes described above canthen, if desired, be converted into their salts, or salts of thecompounds of formula 1 obtained can then, if desired, be converted intothe free compounds. Corresponding processes are known to the personskilled in the art.

The preparation of benzoyl-1,2,3,6-tetrahydrobenzoic acids,benzoyl-1,2,3,4,5,6-hexahydrobenzoic acids,2-[1-(2,3-dihydro-benzofuran-4-yl)-methanoyl]-cyclohexane carboxylicacids or -cyclohexene carboxylic acids is known to the person skilled inthe art (see for example Starting compounds and Intermediates).

1-(2-chloro-ethanoyl)-pyrrolidine-2,5-dione is commercially available.1-(3-chloro-propanoyl)-pyrrolidine-2,5-dione,1-(4-chloro-butanoyl)-pyrrolidine-2,5-dione or1-(5-chloro-pentanoyl)-pyrrolidine-2,5-dione can be prepared accordingto processes known to the person skilled in the art; for example byreaction of the chloroalkanoyl chloride with the pyrrolidine-2,5-dionesodium, potassium or lithium salt in an inert solvent like for exampletetrahydrofurane.

Suitably, the conversions are carried out analogous to methods which arefamiliar per se to the person skilled in the art, for example, in themanner which is described in the following examples.

The substances according to the invention are isolated and purified in amanner known per se, e.g. by distilling off the solvent in vacuo andrecrystallising the residue obtained from a suitable solvent orsubjecting it to one of the customary purification methods, such ascolumn chromatography on a suitable support material.

Salts are obtained by dissolving the free compound in a suitable solvent(for example a ketone like acetone, methylethylketone, ormethylisobutylketone, an ether, like diethyl ether, tetrahydrofuran ordioxane, a chlorinated hydrocarbon, such as methylene chloride orchloroform, or a low molecular weight aliphatic alcohol, such asethanol, isopropanol) which contains the desired acid, or to which thedesired acid is then added. The salts are obtained by filtering,reprecipitating, precipitating with a non-solvent for the addition saltor by evaporating the solvent. Salts obtained can be converted bybasification into the free compounds which, in turn, can be convertedinto salts. In this manner, pharmacologically non-tolerable salts can beconverted into pharmacologically tolerable salts.

The following examples illustrate the invention in greater detail,without restricting it. As well, further compounds of formula 1, ofwhich the preparation is not explicitly described, can be prepared in ananalogous way or in a way which is known by a person skilled in the artusing customary preparation methods.

The compounds, which are mentioned in the examples as well as theirsalts are preferred compounds of the invention.

In the examples, RT stands for room temperature, h for hour(s), min forminute(s) and M. p. for melting point.

EXAMPLES

Final Products

1.1-(2-{4-[(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-yl]-piperidin-1-yl}-2-oxo-ethyl)-pyrrolidine-2,5-dione

A mixture of 1 g of starting compound A1, 0.4 g of succinimide and 1 gof potassium carbonate in 20 ml of dimethylformamide is stirred for 18 hat RT, after which the mixture is diluted with 100 ml of ethyl acetate.After filtering this mixture, the solvent is evaporated and the residuepurified by chromatography (ethyl acetate:methanol/2:1). The titlecompound is crystallized from ethyl acetate. M. p. 171–173° C.

Alternative Synthesis:

A mixture of 5 mmol of starting compound A2, 6 mmol of1-(2-chloro-ethanoyl)-pyrrolidine-2,5-dione and 20 mmol of potassiumcarbonate in 20 ml of dimethylformamide is stirred at RT. After 18 h 100ml of water and 300 ml of diethyl ether is added to the mixture. Theether solution is dried over magnesium sulfate. On concentrating thesolution, the title compound crystallized. M. p. 171–173° C.

In a further alternative ethyl acetate is used instead of diethyl etherin the working up of the above mentioned alternative synthesis.

Starting Compounds and Intermediates

A1.(4aS,8aR)-2-[1-(2-Chloro-ethanoyl)-piperidin-4-yl]-4-(3,4-dimethoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazine-1-one

A solution of 10 g of chloroacetylchloride in 100 ml of dichloromethaneis added slowly to a solution of 10 g of starting compound A2 and 20 mlof triethylamine in 100 ml of dichloromethane at 0° C. After completeaddition, water is added to the reaction and the resulting mixture isstirred for 30 min. The dichloromethane layer is separated and washedwith aqueous sodium carbonate. After drying and evaporating, thecompound is purified by chromatography (ethyl acetate:petroleum ether(60-80° C.)/1:1) and crystallized from diethyl ether. M. p. 104–106° C.

A2.(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-2-piperidin-yl-4-a,5,8,8a-tetrahydro-2H-phthalazin-1-onehydrochloride

A solution of 50 mmol of the salt of (S)-(−)-α-methylbenzylamine and(cis)-2-(3,4-dimethoxybenzoyl)-1,2,3,6-tetrahydrobenzoic acid (startingcompound A8), 55 mmol of piperidin-4-yl-hydrazine dihydrochloride and100 mmol of triethylamine in 150 ml of 1-propanol is refluxed for 18 h.After cooling to RT, the precipitate is filtered off and dried. M. p.285–288° C.

A3.(4aS,8aR)-4-(3,4-Diethoxy-phenyl)-2-piperidin-4-yl-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onehydrochloride

Prepared from the salt of (S)-(−)-α-methylbenzylamine and(cis)-2-(3,4-diethoxybenzoyl)-1,2,3,6-tetrahydrobenzoic acid (startingcompound A9) in 2-propanol as described for compound A2. M. p. 248–250°C.

A4.(cis)-4-(7-Methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-2-piperidin-4-yl-4a,5,8,8a-tetrahydro-2H-phthalazine-1-onehydrochloride

Prepared from(cis)-2-(2,3-Dihydro-2,2-dimethyl-7-methoxybenzofuran-4-carbonyl)-1,2,3,6-tetrahydrobenzoiacid (starting compound A10) in 1-propanol as described for compound A2.After evaporating the solvent, the residue is partitioned betweendichloromethane and aqueous sodium carbonate. The dichlormethane layeris dried over magnesium sulfate and evaporated. The residue is dissolvedin dichloromethane and after the addition of a solution of hydrochloricacid in ether, the compound precipitates. M. p. 288–290° C.

A5. Piperidin-4-yl-hydrazine dihydrochloride

A mixture of 0.1 mole of4-(N′-tert-Butoxycarbonyl-hydrazino)-piperidine-1-carboxylic acidtert-butyl ester (starting compound A6) and 150 ml of concentratedhydrochloric acid is heated at 90° C. for 60 min after which the clearsolution is evaporated. The residue is washed with tetrahydrofurane,filtered off and dried under vacuum. M. p. 256–259° C.

A6. 4-(N′-tert-Butoxycarbonyl-hydrazino)-piperidine-1-carboxylic acidtert-butyl ester

150 ml of a solution of borohydride in tertahydrofurane (1.0 mol/l) isslowly added to a solution of 0.12 mole of4-(tert-Butoxycarbonyl-hydrazono)-piperidine-1-carboxylic acidtert-butyl ester (starting compound A7) in 100 ml of drytetrahydrofurane. After complete addition, the mixture is stirred foranother 30 min after which a 100 ml of water is added to destroy theexcess of borohydride. Subsequently the tetrahydrofurane is evaporatedand the resulting aqeous solution extracted with diethyl ether. Afterdrying the solvent over magnesium sulfate, the ether is evaporated. M.p. 112–115° C.

A7. 4-(tert-Butoxycarbonyl-hydrazono)-piperidine-1-carboxylic acidtert-butyl ester

A mixture of 0.15 mole of 4-oxo-piperidine-1-carboxylic acid tert-butylester (commercially available) and 0.15 mole of tert-butylcarbazate in250 ml of hexane is stirred for 18 h at RT. The precipitate is filteredoff and dried under vacuum. M. p. 172–174° C.

A8. (cis)-2-(3,4-Dimethoxybenzoyl)-1,2,3,6-tetrahydrobenzoic acid

Prepared as described in WO98/31674.

A9. (cis)-2-(3,4-diethoxybenzoyl)-1,2,3,6-tetrahydrobenzoic acid

Prepared as described in WO99/47505.

A10.(cis)-2-(2,3-Dihydro-2,2-dimethyl-7-methoxybenzofuran-4-carbonyl)-1,2,3,6-tetrahydrobenzoicacid

Prepared as described in WO99/31090.

Commercial Utility

The compounds according to the invention have useful pharmacologicalproperties which make them industrially utilizable. As selective cyclicnucleotide phosphodiesterase (PDE) inhibitors (specifically of type 4),they are suitable on the one hand as bronchial therapeutics (for thetreatment of airway obstructions on account of their dilating action butalso on account of their respiratory rate- or respiratorydrive-increasing action) and for the removal of erectile dysfunction onaccount of their vascular dilating action, but on the other handespecially for the treatment of disorders, in particular of aninflammatory nature, e.g. of the airways (asthma prophylaxis), of theskin, of the Intestine, of the eyes, of the CNS and of the joints, whichare mediated by mediators such as histamine, PAF (platelet-activatingfactor), arachidonic acid derivatives such as leukotrienes andprostaglandins, cytokines, interleukins, chemokines, alpha-, beta- andgamma-interferon, tumor necrosis factor (TNF) or oxygen free radicalsand proteases. In this context, the compounds according to the inventionare distinguished by a good solubility, a good tolerability and a highpotency in pharmacological in vivo models upon oral administration.

On account of their PDE-inhibiting properties, the compounds accordingto the invention can be employed in human and veterinary medicine astherapeutics, where they can be used, for example, for the treatment andprophylaxis of the following illnesses: acute and chronic (in particularinflammatory and allergen-induced) airway disorders of varying origin(bronchitis, allergic bronchitis, bronchial asthma, emphysema, COPD);dermatoses (especially of proliferative, inflammatory and allergic type)such as psoriasis (vulgaris), toxic and allergic contact eczema, atopiceczema, seborrhoeic eczema, Lichen simplex, sunburn, pruritus in theanogenital area, alopecia greata, hypertrophic scars, discoid lupuserythematosus, follicular and widespread pyodermias, endogenous andexogenous acne, acne rosacea and other proliferative, inflammatory andallergic skin disorders; disorders which are based on an excessiverelease of TNF and leukotrienes, for example disorders of the arthritistype (rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis andother arthritic conditions), disorders of the immune system (AIDS,multiple sclerosis), graft versus host reaction, allograft rejections,types of shock (septic shock, endotoxin shock, gram-negative sepsis,toxic shock syndrome and ARDS (adult respiratory distress syndrome)) andalso generalized inflammations In the gastrointestinal region (Crohn'sdisease and ulcerative colitis); disorders which are based on allergicand/or chronic, immunological false reactions in the region of the upperairways (pharynx, nose) and the adjacent regions (paranasal sinuses,eyes), such as allergic rhinitis/sinusitis, chronic rhinitis/sinusitis,allergic conjunctivitis and also nasal polyps; but also disorders of theheart which can be treated by PDE inhibitors, such as cardiacInsufficiency, or disorders which can be treated on account of thetissue-relaxant action of the PDE inhibitors, such as, for example,erectile dysfunction or colics of the kidneys and of the ureters inconnection with kidney stones. In addition, the compounds of theinvention are useful in the treatment of diabetes insipidus andconditions associated with cerebral metabolic inhibition, such ascerebral senility, senile dementia (Alz-heimer's disease), memoryimpairment associated with Parkinson's disease or multilnfarct dementia;and also illnesses of the central nervous system, such as depressions orarteriosclerotic dementia.

The Invention further relates to a method for the treatment of mammals,including humans, which are suffering from one of the above mentionedillnesses. The method is characterized in that a therapeutically activeand pharmacologically effective and tolerable amount of one or more ofthe compounds according to the invention is administered to the illmammal.

The invention further relates to the compounds according to theinvention for use in the treatment and/or prophylaxis of illnesses,especially the illnesses mentioned.

The invention also relates to the use of the compounds according to theinvention for the production of pharmaceutical compositions which areemployed for the treatment and/or prophylaxis of the illnessesmentioned.

The invention furthermore relates to pharmaceutical compositions for thetreatment and/or prophylaxis of the illnesses mentioned, which containone or more of the compounds according to the invention.

Additionally, the invention relates to an article of manufacture, whichcomprises packaging material and a pharmaceutical agent contained withinsaid packaging material, wherein the pharmaceutical agent istherapeutically effective for antagonizing the effects of the cyclicnucleotide phosphodiesterase of type 4 (PDE4), ameliorating the symptomsof an PDE4-mediated disorder, and wherein the packaging materialcomprises a label or package insert which indicates that thepharmaceutical agent is useful for preventing or treating PDE4-mediateddisorders, and wherein said pharmaceutical agent comprises one or morecompounds of formula 1 according to the invention. The packagingmaterial, label and package insert otherwise parallel or resemble whatis generally regarded as standard packaging material, labels and packageinserts for pharmaceuticals having related utilities.

The pharmaceutical compositions are prepared by processes which areknown per se and familiar to the person skilled in the art. Aspharmaceutical compositions, the compounds according to the invention(=active compounds) are either employed as such, or preferably incombination with suitable pharmaceutical auxiliaries and/or excipients,e.g. in the form of tablets, coated tablets, capsules, caplets,suppositories, patches (e.g. as TTS), emulsions, suspensions, gels orsolutions, the active compound content advantageously being between 0.1and 95% and where, by the appropriate choice of the auxiliaries and/orexcipients, a pharmaceutical administration form (e.g. a delayed releaseform or an enteric form) exactly suited to the active compound and/or tothe desired onset of action can be achieved.

The person skilled in the art is familiar with auxiliaries or excipientswhich are suitable for the desired pharmaceutical formulations onaccount of his/her expert knowledge. In addition to solvents, gelformers, ointment bases and other active compound excipients, forexample antioxidants, dispersants, emulsifiers, preservatives,solubilizers, colorants, complexing agents or permeation promoters, canbe used.

The administration of the pharmaceutical compositions according to theInvention may be performed in any of the generally accepted modes ofadministration available in the art. Illustrative examples of suitablemodes of administration include intravenous, oral, nasal, parenteral,topical, transdermal and rectal delivery. Oral delivery is preferred.

For the treatment of disorders of the respiratory tract, the compoundsaccording to the invention are preferably also administered byinhalation in the form of an aerosol; the aerosol particles of solid,liquid or mixed composition preferably having a diameter of 0.5 to 10μm, advantageously of 2 to 6 μm.

Aerosol generation can be carried out, for example, by pressure-drivenjet atomizers or ultrasonic atomizers, but advantageously bypropellant-driven metered aerosols or propellant-free administration ofmicronized active compounds from inhalation capsules.

Depending on the inhaler system used, in addition to the activecompounds the administration forms additionally contain the requiredexcipients, such as, for example, propellants (e.g. Frigen in the caseof metered aerosols), surface-active substances, emulsifiers,stabilizers, preservatives, flavorings, fillers (e.g. lactose in thecase of powder inhalers) or, if appropriate, further active compounds.

For the purposes of inhalation, a large number of apparatuses areavailable with which aerosols of optimum particle size can be generatedand administered, using an inhalation technique which is as right aspossible for the patient. In addition to the use of adaptors (spacers,expanders) and pear-shaped containers (e.g. Nebulator®, Volumatic®), andautomatic devices emitting a puffer spray (Autohaler®), for meteredaerosols, in particular In the case of powder inhalers, a number oftechnical solutions are available (e.g. Diskhaler®, Rotadisk®,Turbohaler® or the inhaler described in European Patent Application EP 0505 321), using which an optimal administration of active compound canbe achieved.

For the treatment of dermatoses, the compounds according to theinvention are in particular administered in the form of thosepharmaceutical compositions which are suitable for topical application.For the production of the pharmaceutical compositions, the compoundsaccording to the invention (=active compounds) are preferably mixed withsuitable pharmaceutical auxiliaries and further processed to givesuitable pharmaceutical formulations. Suitable pharmaceuticalformulations are, for example, powders, emulsions, suspensions, sprays,oils, ointments, fatty ointments, creams, pastes, gels or solutions.

The pharmaceutical compositions according to the invention are preparedby processes known per se. The dosage of the active compounds is carriedout in the order of magnitude customary for PDE inhibitors. Topicalapplication forms (such as ointments) for the treatment of dermatosesthus contain the active compounds in a concentration of, for example,0.1–99%. The dose for administration by inhalation is customarly between0.1 and 3 mg per day. The customary dose in the case of systemic therapy(p.o. or i.v.) is between 0.03 and 3 mg/kg per day.

Biological Investigations

The second messenger cyclic AMP (cAMP) is well-known for inhibitinginflammatory and Immunocompetent cells. The PDE4 isoenzyme is broadlyexpressed in cells involved in the initiation and propagation ofinflammatory diseases (H Tenor and C Schudt, in “PhosphodiesteraseInhibitors”, 21–40, “The Handbook of Immunopharmacology”, AcademicPress, 1996), and its inhibition leads to an increase of theintracellular cAMP concentration and thus to the inhibition of cellularactivation (JE Souness et al., Immunopharmacology 47: 127–162, 2000).

The antiinflammatory potential of PDE4 inhibitors in vivo in variousanimal models has been described (MM Teixeira, TiPS 18: 164–170, 1997).For the investigation of PDE4 inhibition on the cellular level (invitro), a large variety of proinflammatory responses can be measured.Examples are the superoxide production of neutrophilic (C Schudt et al.,Arch Pharmacol 344: 682–690, 1991) or eosinophilic (A Hatzelmann et al.,Brit J Pharmacol 114: 821–831, 1995) granulocytes, which can be measuredas luminol-enhanced chemiluminescence, or the synthesis of tumornecrosis factor-α in monocytes, macro-phages or dendritic cells (Gantneret al., Brit J Pharmacol 121: 221–231, 1997, and Pulmonary PharmacolTherap 12: 377–386, 1999). In addition, the immunomodulatory potentialof PDE4 inhibitors is evident from the inhibition of T-cell responseslike cytokine synthesis or proliferation (DM Essayan, Biochem Pharmacol57: 965–973, 1999). Substances which inhibit the secretion of theaforementioned proinflammatory mediators are those which inhibit PDE4.PDE4 inhibition by the compounds according to the invention is thus acentral indicator for the suppression of inflammatory processes.

Method for Measuring Inhibition of PDE4 Activity

PDE4 activity was determined as described by Thompson et al. (Adv CyclNucl Res 10: 69–92, 1979) with some modifications (Bauer and Schwabe,Naunyn-Schmiedeberg's Arch Pharmacol 311: 193–198, 1980). At a finalassay volume of 200 μl (96well microliter plates) the assay mixturecontained 20 mM Tris (pH 7.4), 5 mM MgCl₂, 0.5 μM cAMP, [³H]CAMP (about30,000 cpm/assay), the test compound and an aliquot of cytosol fromhuman neutrophils which mainly contains PDE4 activity as described bySchudt et al. (Naunyn-Schmiedeberg's Arch Pharmacol 344: 682–690, 1991);the PDE3-specific inhibitor Motapizone (1 μM) was included to suppressPDE3 activity originating from contaminating platelets. Serial dilutionsof the compounds were prepared in DMSO and further diluted 1:100 (v/v)in the assays to obtain the desired final concentrations of theInhibitors at a DMSO concentration of 1% (v/v) which by itself onlyslightly affected PDE4 activity.

After preincubation for 5 min at 37° C., the reaction was started by theaddition of substrate (cAMP) and the assays were incubated for further15 min at 37° C. 50 μl of 0.2 N HCl was added to stop the reaction andthe assays were left on ice for about 10 min. Following incubation with25 μg 5′-nucleotidase (Crotalus atrox snake venom) for 10 min at 37° C.,the assays were loaded on QAE Sephadex A-25 (1 ml bed volume). Thecolumns were eluted with 2 ml of 30 mM ammonium formiate (pH 6.0) andthe eluate was counted for radioactivity. Results were corrected forblank values (measured in the presence of denatured protein) which werebelow 5% of total radioactivity. The amount of cyclic nucleotideshydrolyzed did not exceed 30% of the original substrate concentration.The IC₅₀-values for the compounds according to the invention for theinhibition of the PDE4 activity were determined from theconcentration-inhibition curves by nonlinear-regression.

The inhibitory values determined for the compounds according to theinvention follow from the following table A, in which the numbers of thecompounds correspond to the numbers of the examples.

TABLE A Inhibition of PDE4 activity [measured as −logIC₅₀ (mol/l)]compound −logIC₅₀ 1 10.66

1. A compound of formula I

in which R1 and R2 are both hydrogen or together form an additionalbond, R3 represents a phenyl derivative of formulae (a) or (b)

wherein R4 is 1–4C-alkoxy or 1–4C-alkoxy which is completely orpredominantly substituted by fluorine, R5 is 1–4C-alkoxy,3–7C-cycloalkoxy, 3–7C-cycloalkylmethoxy, or 1–4C-alkoxy which iscompletely or predominantly substituted by fluorine, R6 is 1–4C-alkoxyor 1–4C-alkoxy which is completely or predominantly substituted byfluorine, R7 is 1–4C-alkyl and R8 is hydrogen or 1–4C-alkyl, or whereinR7 and R8 together, and with inclusion of the two carbon atoms to whichthey are bonded, form a spiro-linked 5-, 6- or 7-membered hydrocarbonring, optionally interrupted by an oxygen or sulfur atom, R9 is—C(O)—(CH₂)_(n)-R10, wherein R10 is pyrrolidine-2,5-dione-1-yl, n is aninteger from 1 to 4, or a salt thereof.
 2. A compound of formula Iaccording to claim 1 in which R1 and R2 are both hydrogen or togetherform an additional bond, R3 represents a phenyl derivative of formulae(a) or (b)

wherein R4 is 1–2C-alkoxy or 1–2C-alkoxy which is completely orpredominantly substituted by fluorine, R5 is 1–2C-alkoxy or 1–2C-alkoxywhich is completely or predominantly substituted by fluorine, R6 is1–2C-alkoxy or 1–2C-alkoxy which is completely or predominantlysubstituted by fluorine, R7 is methyl and R8 is hydrogen, or wherein R7and R8 together, and with inclusion of the two carbon atoms to whichthey are bonded, form a spiro-linked cyclopentane, cyclohexane,tetrahydrofurane or tetrahydropyran ring, R9 is —C(O)—(CH₂)_(n)-R10,wherein R10 is pyrrolidine-2,5-dione-1-yl, n is an integer from 1 to 2,or a salt thereof.
 3. A compound of formula I according to claim 1 inwhich R1 and R2 together form an additional bond, R3 represents a phenylderivative of formula (a)

wherein R4 is 1–2C-alkoxy, R5 is 1–2C-alkoxy, R9 is —C(O)—(CH₂)_(n)R10,wherein R10 is pyrrolidine-2,5-dione-1-yl and n is 1, or a salt thereof.4. A compound of formula I according to claim 1 in which R1 and R2together form an additional bond, R3 represents a phenyl derivative offormula (a)

wherein R4 is methoxy, R5 is methoxy, R9 is —C(O)—(CH₂)_(n)-R10, whereinR10 is pyrrolidine-2,5-dione-1-yl and n is 1, or a salt thereof.
 5. Acompound of formula I according to claim 1, in which the hydrogen atomsin the positions 4a and 8a are cisconfigurated, or a salt thereof.
 6. Acompound of formula I according to claim 1, in which the absoluteconfiguration is S in the position 4a and R in the position 8a, or asalt thereof.
 7. A compound of formula I according to claim 1 with thechemical formula


8. A compound of formula I according to claim 1 with the chemicalformula

or a salt thereof.
 9. A compound of formula I according to claim 1 withthe chemical name1-(2-{4-[(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2yl]-piperidin-1-yl}-2-oxo-ethyl)-pyrrolidine-2,5-dione.10. A compound of formula I according to claim 1 with the chemical name1-(2-{4-[(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-2-oxo-ethyl)-pyrrolidine-2,5-dioneor a salt thereof.
 11. A process of preparing a compound comprisingreacting(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-2-piperidin-4-yl-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onehydrochloride with 1-(2chloro-ethanoyl)pyrrolidine-2,5-dione in thepresence of a base.
 12. A process of preparing 1-(2-{4[(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2yl]-piperidin-1-yl}-2oxo-ethyl)-pyrrolidine-2,5-dionecomprising reacting (4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-2-piperidin-4-yl-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onehydrochloride with 1-(2-chloro-ethanoyl)-pyrrolidine-2,5-dione in thepresence of a base.
 13. A pharmaceutical composition comprising one ormore compounds of formula I according to claim 1, or a pharmaceuticallyacceptable salt thereof, together with a suitable pharmaceuticalauxiliary and/or excipient.
 14. A method for treating airway disordersin a patient comprising administering to said patient a therapeuticallyeffective amount of a compound of formula I as claimed in claim 1, or apharmaceutically acceptable salt thereof.
 15. A compound of formula Iaccording to claim 2, in which the hydrogen atoms in the positions 4aand 8a are cis-configurated, or a salt thereof.
 16. A compound offormula I according to claim 2, in which the absolute configuration is Sin the position 4a and R in the position 8a, or a salt thereof.
 17. Acompound of formula I according to claim 3, in which the hydrogen atomsin the positions 4a and 8a are cisconfigurated, or a salt thereof.
 18. Acompound of formula I according to claim 3, in which the absoluteconfiguration is S in the position 4a and R in the position 8a, or asalt thereof.
 19. A compound of formula I according to claim 4, in whichthe hydrogen atoms in the positions 4a and 8a are cis-configurated, or asalt thereof.
 20. A compound of formula I according to claim 4, in whichthe absolute configuration is S in the position 4a and R in the position8a, or a salt thereof.
 21. The method according to claim 14, wherein theairway disorder is selected from the group consisting of bronchitis,allergic bronchitis, bronchial asthma, emphysema, COPD and allergicrhinitis.
 22. A method for treating dermatoses in a patient comprisingadministering to said patient a therapeutically effective amount of acompound of formula I as claimed in claim 1, or a pharmaceuticallyacceptable salt thereof.
 23. The method according to claim 22, whereinthe dermatose is selected from the group consisting of psoriasis andatopic eczema.
 24. A pharmaceutical composition comprising the compoundof claim 7 together with a suitable pharmaceutical auxiliary and/orexcipient.
 25. A pharmaceutical composition comprising the compound ofclaim 8, or a pharmaceutically acceptable salt thereof, together with asuitable pharmaceutical auxiliary and/or excipient.
 26. A method fortreating airway disorders in a patient comprising administering to saidpatient a therapeutically effective amount of the compound of claim 7.27. A method for treating airway disorders in a patient comprisingadministering to said patient a therapeutically effective amount of thecompound of claim 8 or a pharmaceutically acceptable salt thereof. 28.The method according to claim 26, wherein the airway disorder isselected from the group consisting of bronchitis, allergic bronchitis,bronchial asthma, emphysema, COPD and allergic rhinitis.
 29. The methodaccording to claim 27, wherein the airway disorder is selected from thegroup consisting of bronchitis, allergic bronchitis, bronchial asthma,emphysema, COPD and allergic rhinitis.
 30. A method for treatingdermatoses in a patient comprising administering to said patient atherapeutically effective amount of the compound of claim
 7. 31. Amethod for treating dermatoses in a patient comprising administering tosaid patient a therapeutically effective amount of the compound of claim8 or a pharmaceutically acceptable salt thereof.
 32. The methodaccording to claim 30, wherein the dermatose is selected from the groupconsisting of psoriasis and atopic eczema.
 33. The method according toclaim 31, wherein the dermatose is selected from the group consisting ofpsoriasis and atopic eczema.